1. Field of the Invention
The present invention relates to a novel organic acid salt of amlodipine (2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1, 4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester), a preparation method thereof and a pharmaceutical composition comprising the same as an active ingredient.
2. Description of the Related Art
Amlodipine having a calcium channel blocking activity is useful in treating hypertension. As disclosed in EP 089 167, amlodipine is used in the form of salts formed with acids capable of forming non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, hydrochloride, hydrobromide, sulphate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate and gluconate salts. U.S. Pat. No. 6,291,490 discloses S-(−)-amlodipine that avoids the concomitant liability of adverse effects associated with the racemic mixture of amlodipine.
U.S. Pat. No. 4,879,303 discloses amlodipine besylate that satisfies the following physiochemical criteria: (1) good solubility; (2) good stability; (3) non-hygroscopicity; (4) processability for tablet formulation, etc.
However, amlodipine besylate has relatively low solubility at pH 1˜7.4. Thus, there has been increasing demand for other salt forms for amlodipine having improved solubility. Also, amlodipine besylate, which is very unstable against light, has a problem in that it may produce various decomposed products.
Benzene sulfonic acid used in preparing amlodipine besylate is disadvantageously corrosive and noxious to be used for industrial purposes. Also, since benzene sulfonic acid is highly hygroscopic, it requires great care during transport and handling. Further, benzene sulfonic acid is unfavorably used in the form of dense oily material containing 90% of acid and 10% of water, as disclosed in WO 99/52873. To overcome these disadvantages, there has been proposed use of benzene sulfonic acids in the form of an ammonium salt. However, toxic ammonia gas generated during preparation of amlodipine besylate requires additional steps of absorbing and inactivating the toxic ammonia gas, which is also described in WO 99/52873.